Abstract Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce 2019 coronavirus disease (COVID-19), which progresses to acute respiratory distress syndrome and death in a significant proportion of patients. As outlined in the Notice of Special Interest NOT-AI-20-030, there is a critical lack of understanding of many fundamentals of COVID-19. It is urgent that we determine the mechanism of acute lung injury caused by SARS-CoV-2 infection and how this might be prevented therapeutically. Many lines of investigation suggest that acute respiratory distress syndrome experienced in severe COVID-19 is due to an overwhelming host innate immune response. This provides an opportunity to block the innate response therapeutically and offset severe disease. Lethal COVID-19 is associated with marked lung inflammation and alveolar disruption, suggesting that alveolar cells die by pyroptosis, an intensely inflammatory form of cell death. Pyroptosis is mediated by activated inflammatory caspases and cleaved gasdermin D (GSDMD), and pharmacologic inhibitors of these two essential factors have been developed. Based on these findings, we hypothesize that acute lung injury caused by SARS-CoV-2 infection in humans is mediated by intense inflammation and pyroptosis, and that inhibitors of inflammatory caspases and GSDMD will block lung damage. Importantly, the PI has federal and university clearance to work with highly pathogenic viruses such as SARS- CoV-2 in the University of Pittsburgh?s Regional Biocontainment Laboratory, where he has exclusive use of a laboratory suite. We will use precision-cut human lung slices, which are a powerful tool to study pathogenic human viruses in the context of the intact, human lung. We are already using this system to evaluate acute lung injury caused by highly pathogenic avian influenza (H5N1), which causes acute respiratory distress syndrome in humans similar to severe COVID-19. We have recently found that alveolar cells infected with H5N1 influenza die by pyroptosis which is prevented by VX-765 and disulfiram, inhibitors of caspase-1/4 and GSDMD, respectively. Notably, both drugs have been shown to be safe in humans. Disulfiram in particular is widely used to treat other human conditions and is extremely cheap and readily available. In this proposal, we will first determine the cellular targets of SARS-CoV-2 infection in human lung, and then determine how alveolar cells die following infection. We will then determine if innate immune inhibitors targeting caspase-1/4 and GSDMD prevent alveolar cell damage. If we determine that acute lung injury caused by SARS-CoV-2 is prevented by VX-765 and disulfiram, our study would justify the clinical use of these drugs to prevent severe COVID-19 in this expanding pandemic, which would be a major public health breakthrough.